Stabilized transdermal drug delivery system

ABSTRACT

A solid dispersion transdermal drug delivery system comprising a therapeutic agent in a stable amorphous form and a combination polymeric stabilizing and dispersing agent having a hydrogen bond-forming functional group, and a method of manufacturing these systems is provided. The weight ratio of the combination polymeric stabilizing and dispersing agent to the therapeutic agent is also disclosed.

This application claims priority to U.S. Provisional Application61/057,455, which was filed May 30, 2008, and is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a solid dispersion transdermal drugdelivery system comprising a therapeutic agent in a stable amorphousform and a polymeric stabilizer capable of hydrogen bonding with thetherapeutic agent, and to a method of manufacturing these systems.Further, the present invention relates to the importance of the weightratio of the polymeric stabilizer to the therapeutic agent instabilizing the therapeutic agent.

BACKGROUND OF THE INVENTION

Transdermal drug delivery, delivery of drugs through the skin, providesmany advantages. Primarily, it is a comfortable, convenient andnon-invasive way of administering drugs. Drugs delivered transdermallydirectly enter subdermal blood vessels, and are transported to thetarget site via by-passing the first-pass liver metabolism anddecomposition. This method allows for high drug bioavailability. Thesystem requires a relatively small amount of drug and can be aneffective method for sustained drug delivery, allowing for a reducedfrequency of administration. Moreover, such a means of delivery providesuninterrupted therapy and a higher degree of control over drugconcentrations in the blood. These characteristics help avoid sideeffects caused by temporarily high blood concentrations of drugs whichaccompany administration of oral dosage forms and injections.

The outer layer of the skin called the stratum corneum, however, forms abarrier to drug absorption for almost all compounds and often preventsthe delivery of an effective amount of the drug. Due to the hydrophobicnature of the stratum corneum, absorption of the hydrophilic salts ofdrugs is especially difficult. Large molecules and extremely hydrophobicdrugs also have difficulty being absorbed through the skin.

Chemical enhancers are commonly used to overcome the stratum corneumbarrier. These enhancers, however, can introduce side effects such asskin irritation and formulation incompatibility and often still can notincrease drug absorption sufficiently to meet the drug's therapeuticdose requirement.

Additionally, physical means are a common method used to overcome thestratum corneum barrier function. These means include iontophoresis,electroporation, sonophoresis, and skin micro abrasion.

U.S. Pat. No. 4,409,206 discloses a preparation in the form of apolyacrylate film with an amorphous active pharmaceutical ingredientembedded therein.

United States Publication No. 2005/0064022 describes a terazosintransdermal device and methods of use. The publication discloses thepreparation of terazosin in amorphous form by spray drying, rollerdrying and freeze drying prior to incorporation into the transdermaldelivery device. More specifically, the publication discloses atransdermal therapeutic system for the administration of amorphousterazosin to the skin, comprising a backing layer, a pressure-sensitiveadhesive reservoir layer and/or a matrix layer, and optionally aremovable protective layer.

United States Publication No. 2005/0175678 is directed to a polymermatrix suitable for the transdermal administration of rotigotine and amethod of preparing the same. The polymer matrix contains asupersaturated amount of a rotigotine base such that the portion of therotigotine that is not dissolved in the matrix polymeric adhesive isdispersed in the adhesive matrix as amorphous particles. The publicationfurther discloses that the matrix adhesive may be a component of asystem for transdermal administration of rotigotine, wherein the systemcan have components such as a protective layer, a backing layer, furtherpolymeric adhesive layers, and/or a membrane which controls the releaseof the rotigotine.

U.S. Pat. No. 6,902,741 is directed to a transdermal system whichincludes a sex hormone-containing adhesive matrix, containing inclusionsof sex hormone in a hydrophilic non-crosslinked polymer. The active sexhormone contained in the inclusions is preferably amorphous to an extentof more than 50% by weight of the active substance. The active sexhormone-containing laminate is characterized in that the active sexhormone inclusions are contained in the adhesive matrix in dissolved ordispersed form and that the active sex hormone inclusions arepre-prepared prior to incorporation to the adhesive matrix. Thus theprocess requires a step of pre-preparation of the active hormoneinclusion, followed by another step of incorporating the inclusions toan adhesive matrix polymer solution.

Various methods of manufacturing transdermal systems in which the drugis supersaturated are known. U.S. Pat. Nos. 4,409,206, 4,490,322,4,797,284, 4,880,633, 5,352,457 5,869,089, 5,906,830, 6,153,216,6,156,335, and 6,623,763 describe methods of manufacturing transdermalsystems. U.S. Pat. No. 4,490,332 discloses a method of manufacturing apolyacrylate film for long term transdermal administration by forming asolution of a pharmaceutical and a freeze-dried latex polyacrylatecopolymer in a solvent. U.S. Pat. No. 5,906,830 discloses a method ofmanufacturing a supersaturated transdermal system comprising heating amixture of undissolved drug and reservoir matrix material to apredetermined temperature, followed by cooling.

Scopolamine is a difficult molecule to administer transdermally as themolecule recrystallizes in both laminate and patch delivery systems. Asthis recrystallization occurs, the delivery rate is reduced. SeveralU.S. Pat. Nos. 4,832,953, 5,662,928, 6,569,448, 6,238,700 describe anannealing method to anneal laminates and patches for removal orprevention of formation of crystalline scopolamine or their hydrates.These processes are tedious, complex and costly.

Oxybutynin is also a troublesome molecule for transdermal delivery. U.S.Pat. No. 5,164,190 discloses transdermal administration of hydrophobicdrugs via a diffusion mechanism in which the drug is dissolved in acarrier at concentrations between 20% and 80% of saturationconcentration. U.S. Patent Application No. 2004/0057985 discloses atransdermal system wherein a matrix layer comprises two phases which areimmiscible with each other, namely an inner phase and an outer phase.

U.S. Patent Application No. 2004/0081683 discloses a transdermal systemcontaining a self-adhesive matrix consisting of an adhesive polymer andan amine functional drug including oxybutynin and is free of particlesthat absorb salts of amine functional drugs.

Naltrexone is poorly absorbed through the skin and therefore prodrugshave been developed to enhance the skin absorption. The absorption rateof the prodrugs, however, is still insufficient to achieve therapeuticdosages.

Testosterone is also poorly absorbed from the skin even in the presenceof a high level of enhancers.

Although the required therapeutic dose is low, the transdermal deliveryrate of crystalline estradiol often can not achieve the therapeuticlevel.

Thus there remains a need for a stable transdermal system which canimprove the absorption rate through the skin for various therapeuticagents.

SUMMARY OF THE INVENTION

In accordance with the present invention, a solid dispersion transdermaldrug delivery system is provided which has an improved stability andabsorption rate from the skin for various therapeutic agents. Thetransdermal drug delivery system of the invention, includes a stableamorphous form of a therapeutic agent, and a polymeric stabilizer whichis also a dispersant capable of forming hydrogen bonding with thetherapeutic agent. The transdermal drug delivery system of the inventionis further characterized by the long-term stability of the therapeuticagent dependent upon the ratio of the therapeutic agent to the polymericstabilizer.

The transdermal drug delivery system of the present invention furthercomprises at least three layers: a backing film, an adhesive layer, anda protective release liner. The adhesive layer comprises an adhesive, atherapeutic agent in amorphous form, and a combination polymericstabilizing and dispersing agent comprising a hydrogen bond-formingfunctional group and a protective release liner.

The invention is particularly adapted to transdermal drug deliverysystems wherein the therapeutic agent may be, for example, (i)scopolamine, oxybutynin, naltrexone, testosterone, estradiol,rotigotine, fentanyl, ethinyl estradiol, or norelgestral (ii) anypharmaceutically acceptable salts of any of (i), or any combination ofany of (i), (ii), or (i) and (ii).

Another embodiment of the invention includes a fourth layer. This secondadhesive layer, or skin contact adhesive layer, is also comprised of anadhesive, a therapeutic agent in amorphous form, and combinationpolymeric stabilizing and dispersing agent comprising a hydrogenbond-forming functional group. The second adhesive layer resides betweenthe first adhesive layer (a drug reservoir adhesive layer) and theprotective release liner. The second adhesive may be the same as ordifferent from the first adhesive, and the second therapeutic agent inamorphous form may be the same as or different from the firsttherapeutic agent. The second combination polymeric stabilizing anddispersing agent may be the same as or different from said firstcombination polymeric stabilizing and dispersing agent.

Another embodiment of the invention includes a fifth layer. The fifthlayer comprises a membrane which resides between the drug reservoiradhesive layer and the skin contact adhesive layer.

In another embodiment of the invention, the adhesive layer (the drugreservoir adhesive layer and/or the skin contact adhesive layer) mayadditionally include a skin penetration enhancer, tackifier, and/orcohesive promoter.

In accordance with the present invention, the amorphous form of atherapeutic agent which contains at least one hydrogen bond-forminggroup remains stable for a long period of time when it is dispersedwithin a polymeric material matrix which also contains at least onehydrogen bond-forming group. The hydrogen bond association between themolecules of the therapeutic agent and the polymeric material alsoprovides additional dispersion capability. The greater dispersioncapability is compared to an identical drug delivery device that doesnot have a polymeric stabilizing/dispersing agent. The greaterdispersion capacity may include, for example, an increased amount oftherapeutic agent dispersed in the polymeric material or greateruniformity of the therapeutic agent dispersed through the polymericmaterial as compared to a dispersion without hydrogen bonding.

In accordance with the present invention, the stability of thetherapeutic agent is increased if the weight ratio of the polymericmaterial containing at least one hydrogen bond-forming group to thetherapeutic agent is at least 0.5.

In accordance with the present invention, the stability of thetherapeutic agent in the transdermal drug delivery system ischaracterized by the therapeutic agent's ability to remain amorphousover time without forming crystals.

In one aspect of the present invention, at least 95% of said therapeuticagent is in amorphous form after storage at room temperature for atleast six months. In another aspect of the present invention, at least99% of said therapeutic agent is in amorphous form after storage at roomtemperature for at least six months. In yet another aspect of thepresent invention, at least 99% of said therapeutic agent is inamorphous form after storage at room temperature for at least 18 months.

In another aspect of the present invention, the therapeutic agent has askin absorption rate which is increased by at least 25% compared to theskin absorption rate of the therapeutic agent in an identicaltransdermal drug delivery without said polymeric stabilizing/dispersingagent. In another aspect of the present invention, the absorption rateis increased by at least 50%. In another aspect of the presentinvention, the skin absorption rate is increased by at least 75%.

Additionally, if the therapeutic agent has a low glass transitiontemperature, the weight ratio of the polymeric material to the amorphousform of a therapeutic agent required to disperse the amorphous form ofthe therapeutic agent is 2 or greater. In one aspect of the presentinvention, the low glass transition temperature is less than 50° C. Inanother aspect of the present invention, the low glass transitiontemperature is less than 40° C.

The ratio of the weight of the polymeric material to the amorphous formof a therapeutic agent required to stabilize the amorphous form of atherapeutic agent with a high glass transition temperature is 0.5 orgreater. In one aspect of the present invention, the high glasstransition temperature is at least 60° C. In another aspect of thepresent invention, the high glass transition temperature is at least 70°C. In one aspect of the present invention the ratio of the weight of thepolymeric material to the amorphous form of a therapeutic agent requiredto stabilize the amorphous form of a therapeutic agent with a high glasstransition temperature is between 0.5 and 10; in another aspect, it isbetween 0.5 and 2.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an enlarged, schematic, cross-sectional view of athree-layered transdermal delivery device of the present invention.

FIG. 2 is an enlarged, schematic, cross-sectional view of a four-layeredtransdermal delivery device of the present invention.

FIG. 3 is an enlarged, schematic, cross-sectional view of a five-layeredtransdermal delivery device of the present invention.

DETAILED DESCRIPTION

The present invention is a solid dispersion transdermal drug deliverysystem wherein the system comprises a stable amorphous form oftherapeutic agent and a polymeric stabilizer and dispersant capable offorming hydrogen bonds with the therapeutic agent. Further, thestability of the therapeutic agent of the solid dispersion transdermaldrug delivery system of the invention is enhanced by the optimizing theweight ratio of the therapeutic agent to the polymeric stabilizer. Ithas surprisingly been found that the stability is enhanced by optimizingthe weight ratio of the therapeutic agent to the polymeric stabilizer,and that such optimal ratio is dependent upon the therapeutic agent'sglass transition temperature. As used herein, “transdermal” meansdelivery of an active pharmaceutical ingredient into and through theskin or mucosal tissue. The Figures depict several embodiments of thepresent invention where transdermal delivery devices are in the form ofskin patches that, when applied to skin, function to transdermallydeliver an active pharmaceutical ingredient.

As used herein, the term “glass transition temperature,” or Tg is thetemperature at which a material transitions to a glassy state from aliquid state, as measured at standard atmospheric pressure. A drughaving a high glass transition temperature includes, for example, a drughaving a Tg of at least 60° C. (i.e., 80° C.). A drug having a low glasstransition temperature includes, for example, a drug having a Tg of lessthan 50° C. (i.e., 30° C.).

As used herein, the term “crystalline” and “crystallinity” of atherapeutic agent means that X-ray diffraction patterns of thetherapeutic agent show ordered sharp patterns as opposed to thediffusely scattered X-rays with an amorphous compound. Alternatively,crystallinity can be measured by a technique calibrated to X-raycrystallinity, such as FT-IR, a density column, or DSC. As used herein,the term “amorphous” means that the therapeutic agent is notcrystalline. See, e.g., Remington's Pharmaceutical Sciences, 18^(th) ed.page 173; The United States Pharmacopeia, 23^(rd) ed, (1995) pages1843-1844. Typically, the amorphous therapeutic agents of this inventionhave a crystallinity, as measured by X-ray diffraction, of a less thanabout 5%, preferably less than about 2%, more preferably less than about1%, and most preferably from about 0.5% to 0% crystallinity.

The solid dispersion transdermal drug delivery systems of the presentinvention comprise at least three layers. FIG. 1 depicts a three-layeredtransdermal delivery device 10 comprised of a backing layer 11, anadhesive layer 12 comprising a therapeutic agent in amorphous form, anda stabilizing agent with a hydrogen bond-forming functional groupcapable of hydrogen bonding with the therapeutic agent, and a protectiverelease liner 13. FIG. 2 depicts a four-layered transdermal deliverydevice 20 comprised of a drug reservoir layer 22, and a skin contactlayer 23, each comprising a therapeutic agent in amorphous form and astabilizing agent with a hydrogen bond-forming functional group capableof hydrogen bonding with the therapeutic agent, a backing layer 21, anda protective release liner 24. FIG. 3 depicts a five-layered transdermaldelivery device 30 comprised of a drug reservoir layer 32, and a skincontact layer 34, each comprising a therapeutic agent in amorphous formand a stabilizing agent with a hydrogen bond-forming functional groupcapable of hydrogen bonding with the therapeutic agent, a membrane 33sandwiched between the drug reservoir layer 32 and skin contact layer34, a backing layer 31, and a protective release liner 35.

The outermost layer of these solid dispersion transdermal deliverydevices with respect to the skin is the backing layer, 11, 21, or 31.The backing layer is a flexible substrate which provides a barrieragainst migration of an active pharmaceutical ingredient away from theintended direction of drug delivery and which provides support for thedevice. The composition of the backing layer is not critical. Anywell-known backing layer which possesses these qualities can be used inthe present invention. For example, backing layers composed of thefollowing materials can be employed: polyethylene terephthalate, nylons,polypropylenes, polyesters, polyester/ethylene-vinyl acetate, metalizedpolyester films, polyvinylidene chloride, metal films such as aluminumfoils, polyvinylidene fluoride films, or mixtures or copolymers orlaminates thereof. Specific backing layers which may be utilized includeMediflex® 1200 (available from Mylan Technologies, Inc.), Mediflex®1501, Mediflex® 1502, Mediflex® 1503, and Scotchpak® 1109. Preferred arebacking layers composed of polyethylene and polyester. Most preferred isthe use of Mediflex® 1501 and Mediflex® 1200 as the backing layer.

The thickness of such backing layer is also not critical. Backing layershaving a thickness ranging from about 1 mil to about 10 mils may beutilized in the practice of the present invention. Preferably, backinglayers will have a thickness ranging from about 1.5 mils to about 6mils. Most preferably, the backing layer will have a thickness of about3 mils.

At least one adhesive layer is positioned adjacent to the backing layeron the side of the backing layer to face the patient when the device isapplied. The adhesive layer comprises an adhesive, at least onetherapeutic agent in amorphous form, and a stabilizing agent comprisingat least one hydrogen bond-forming functional group which is capable ofhydrogen bonding with the therapeutic agent. The stabilizing agent alsoacts as a dispersant, thereby increasing the capacity of the adhesivelayer for the therapeutic agent.

The adhesive layer may be a drug reservoir adhesive layer or a skincontact adhesive layer depending on the desired structure of the system,the drug being delivered, and the release characteristics of thetransdermal device. Further, the device may contain one or more of adrug reservoir adhesive layer. While the drug reservoir adhesive layerand the skin contact adhesive layer may contain the same constituentcomponents, the amounts and/or specific types of any one component mayvary between the two layers.

The size and shape of the adhesive layer is not critical and will dependupon the structure and the release characteristics of the device as wellas the drug being delivered. The only limitation is that the adhesivelayer may not extend beyond the backing layer.

The “adhesive material” contained in the adhesive layer may be anybiocompatible polymer or polymeric material known in the art. Forexample, the adhesive material may be selected from silicones, naturaland synthetic rubbers, polyethylene-styrene-ethylene block polymer,polystyrene-butydiene, polyisobutylene (“PIB”), polybutenes, neoprenes,polybutadienes, polyisobutenes, polyisoprenes, polysiloxanes, acrylicadhesives including cross-linked and uncross-linked acrylic copolymers,vinyl acetate adhesives, polyacrylates, ethylenevinylacetate copolymers,styrene-isoprene copolymers, polyurethanes, plasticized weight polyetherblock amide copolymers, plasticized styrene-rubber block copolymers, andmixtures thereof. In embodiments containing more than one adhesivelayer, the type of adhesive material chosen may be the same or differentfor each adhesive layer. Preferably, the adhesive material is selectedfrom the group consisting of polysiloxanes, PIB, and acrylics. Mostpreferably, the adhesive material is one or more polysiloxanes.

The amount of adhesive material present in the at least one adhesivelayer ranges from about 30% to about 95% by weight of the adhesivelayer, preferably ranging from about 35% to about 90% by weight of theadhesive layer, most preferably ranging from about 36% to about 80% byweight of the adhesive layer. In embodiments containing more than oneadhesive layer, the amount of adhesive material may be the same ordifferent for each adhesive layer.

In one preferred embodiment, the adhesive material is PIB. In anotherpreferred embodiment, a PIB blend is used comprising a low molecularweight PIB (about 25,000 to about 50,000 viscosity average molecularweight) and a high molecular weight PIB (about 700,000 to about1,500,000 viscosity average molecular weight). In embodiments where aPIB blend is utilized, the ratio of low molecular weight PIB to highmolecular weight PIB ranges from about 95:5 to about 55:45.

The stabilizing agent contained within the adhesive layer comprises atleast one hydrogen bond-forming functional group which is capable ofhydrogen bonding with the therapeutic agent within the device.Non-limiting examples of hydrogen bond-forming functional groups whichmay be present on the stabilizing agent of the adhesive layer includehydroxyl, lower alkoxy, ether, amino, fluoro, and carbonyl.

The stabilizing agent is a compound or neutral pharmaceutical base thatlowers the rate at which the therapeutic agent degrades, underenvironmental conditions of storage. The stabilizing agent may improvelong-term stability of the therapeutic agent, wherein the term“long-term” includes at least six months. In one aspect, the stabilityover a time of at least 12 months is improved. In one aspect, thestability over a time of at least 18 months is improved. In one aspect,the stability over a time of at least 24 months is improved. In oneembodiment, the improved stability means that less than 5% of thetherapeutic agent is crystalline. In another embodiment, the improvedstability means that less than 1% of the therapeutic agent iscrystalline.

Non-limiting examples of the stabilizing agent used in the adhesivelayer include polyvinylpyrrolidone, poly(vinylpyrrolidone-vinylacetate)copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxyethyl cellulose, ethylcellulose, or a combination thereof. Inpreferred embodiments, the stabilizer is polyvinylpyrrolidone orpoly(vinylpyrrolidone-vinylacetate) copolymer. Most preferably, thestabilizer is polyvinylpyrrolidone.

The amount of stabilizing agent present in the adhesive layer will varyand depend upon the identity of the stabilizing agent and the amount andidentity of the adhesive material and/or the therapeutic agent.Generally, the amount of the stabilizing agent will range from about 2to about 40 wt. % based upon the weight of the adhesive material.Preferably, it will range from about 5 to about 30 wt. % on the samebasis. Most preferably, it will be present in an amount of about 5 to 20wt. % on the same basis or from about 10% to about 20% by weight, eachon the same basis.

The term “therapeutic agent” or “active pharmaceutical ingredient” isused to describe the principal active ingredient of the solidtransdermal delivery device, which is a biologically active compound ormixture of compounds that has a therapeutic, prophylactic and/orphysiological effect on the wearer of the device. It is present in astable amorphous form and forms a solid dispersion with a polymerstabilizer capable of hydrogen bonding with the therapeutic agent.

Non-limiting examples of active pharmaceutical ingredients includeanti-inflammatory substances, opioid receptor antagonists,anticholinergics, coronary dilators, cerebal dilators, peripheralvasodilators, alpha-adrenergic blockers, anti-infectives, psychotropics,anti-manics, stimulants, anti-histamines, decongestants,gastro-intestinal sedatives, anti-anginal drugs, vasodilators,anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors, migrainetreatments, anti-coagulants and anti-thrombotic drugs, analgesics,anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants,anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents,thyroid and anti-thyroid preparations, diuretics, anti-spasmodics,anti-emetic, uterine relaxants, anti-obesity drugs, anabolic drugs,erythropoietic drugs, anti-asthmatics, bronchodilators, expectorants,mucolytics, anti-uricemic drugs and the like.

The therapeutic agent of the adhesive layer is any pharmaceutical activeingredient which contains a hydrogen bond-forming functional group. Suchfunctional groups include, but are not limited to hydroxyl, loweralkoxy, ether, amino, fluoro, and carbonyl. Non-limiting examples ofpreferred therapeutic agents capable of use in the adhesive layerinclude scopolamine, oxybutynin, naltrexone, testosterone, estradiol,rotigotine, fentanyl, ethinyl estradiol, methylphenidate, norelgestraland piroxicam. The references to the therapeutic agents also includetheir salts, solvates, hydrates, prodrugs and derivative compounds ofany of the foregoing. For instance, scopolamine includes the derivativecompound butylscopolamine.

The amount of the therapeutic agent present in the adhesive layer willvary and depend upon, among other factors, its identity, the intendeddosing of the device, the number of adhesive layers present and theamount and identity of the therapeutic agent. Generally, the amount ofthe therapeutic agent will range from about 0.5 to about 40 wt. % basedupon the weight of the adhesive material. Preferably, it will range fromabout 1 to about 25 wt. % on the same basis. Most preferably, it will bepresent in an amount of about 5 to about 15 wt. % on the same basis.

In embodiments containing a single adhesive layer such as depicted inFIG. 1, the amount of active pharmaceutical ingredient present in theadhesive layer ranges from about 1% to about 25% by weight of theadhesive material, preferably ranging from about 5% to about 20% byweight of the adhesive material, and most preferably ranging from about7% to about 9% by weight of the adhesive material.

In embodiments containing two adhesive layers such as depicted in FIGS.2 and 3, the amount of active pharmaceutical ingredient in the drugreservoir adhesive layer ranges from about 1% to about 30% by weight ofthe drug reservoir adhesive material, preferably from about 4% to about20% by weight of the drug reservoir adhesive material, most preferablyfrom about 5% to about 15% by weight of the drug reservoir adhesivematerial. Similarly, in embodiments containing two adhesive layers suchas depicted in FIGS. 2 and 3, the amount of active pharmaceuticalingredient in the skin contact adhesive layer ranges from about 0% toabout 5% by weight of the skin contact adhesive material, preferablyfrom about 2% to about 4% by weight of the skin contact adhesivematerial, most preferably from about 1% to about 2.5% by weight of theskin contact adhesive material.

In one embodiment, the weight ratio of the stabilizing agent to thetherapeutic agent is about 0.5 or greater. The specific ratio used isdependent upon the glass transition temperature of the therapeuticagent. Those therapeutic agents with a lower glass transitiontemperature will remain stable in the transdermal drug delivery systemwhen the ratio of the stabilizing agent to the therapeutic agent is 2 orgreater. Such therapeutic agents with lower relative glass transitiontemperatures, such as scopolamine and oxybutynin, require an increasedamount of stabilizing agent, by weight, to disperse and stabilize thetherapeutic agent. Those therapeutic agents with a higher glasstransition temperature will remain stable in the transdermal drugdelivery system when the ratio of the stabilizing agent to thetherapeutic agent is 0.5 or greater. Such stabilizing agents with higherrelative glass transition temperatures, such as naltrexone, require alower amount of stabilizing agent, by weight, to disperse and stabilizethe therapeutic agent. Therefore, the stability of the therapeutic agentin the transdermal drug delivery system is based upon the correlationbetween the glass transition temperature of the therapeutic agent andweight ratio of the stabilizing agent to the therapeutic agent asinversely proportional.

In the case of scopolamine, the stabilizing agent will generally bepresent in an amount ranging up to about 18 wt. % based upon the weightof the adhesive material. Preferably, it will range up to about 13 wt. %on the same basis. Most preferably, it will be present in an amount ofabout 1 to about 12 wt. % on the same basis. Further, the weight ratioof the stabilizing agent to scopolamine is about 0.5 or greater.Preferably, the weight ratio will be about 2 or greater.

In the case of oxybutynin, the stabilizing agent will generally bepresent in an amount ranging up to about 25 wt. % based upon the weightof the adhesive material. Preferably, it will range up to about 20 wt. %on the same basis. Most preferably, it will be present in an amount ofabout 1 to about 15 wt. % on the same basis. Further, the weight ratioof the stabilizing agent to oxybutynin is about 0.5 or greater.Preferably, the weight ratio will be about 2 or greater.

In the case of naltrexone, the stabilizing agent will generally bepresent in an amount ranging from about 5 to about 25 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 7.5 to about 20 wt. % on the same basis. Most preferably, it willbe present in an amount of about 10 to about 15 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to naltrexone isabout 0.5 or greater. Preferably, the weight ratio of the stabilizingagent to naltrexone is between about 1 and 1.5.

In the case of testosterone, the stabilizing agent will generally bepresent in an amount ranging from about 5 to about 25 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 5 to about 20 wt. % on the same basis. Most preferably, it will bepresent in an amount of about 5 and about 15 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to testosterone isabout 0.5 or greater.

In the case of estradiol, the stabilizing agent will generally bepresent in an amount ranging from about 1 to about 10 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 1 to about 8 wt. % on the same basis. Most preferably, it will bepresent in an amount of about 1 to about 6 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to estradiol is about0.5 or greater.

In the case of rotigotine, the stabilizing agent will generally bepresent in an amount ranging from about 1 to about 20 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 5 to about 15 wt. % on the same basis. Most preferably, it will bepresent in an amount of about 5 to about 10 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to rotigotine isabout 0.5 or greater.

In the case of fentanyl, the stabilizing agent will generally be presentin an amount ranging from about 1 to about 20 wt. % based upon theweight of the adhesive material. Preferably, it will range from about 2to about 10 wt. % on the same basis. Most preferably, it will be presentin an amount of about 2 to about 5 wt. % on the same basis. Further, theweight ratio of the stabilizing agent to fentanyl is about 0.5 orgreater.

In the case of ethinyl estradiol, the stabilizing agent will generallybe present in an amount ranging from about 0.1 to about 10 wt. % basedupon the weight of the adhesive material. Preferably, it will range fromabout 0.2 to about 6 wt. % on the same basis. Most preferably, it willbe present in an amount of about 0.5 to about 5 wt. % on the same basis.

In the case of methylphenidate, the stabilizing agent will generally bepresent in an amount ranging from about 1 to about 25 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 5 to about 20 wt. % on the same basis. Most preferably, it will bepresent in an amount of about 5 to about 15 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to methylphenidate isabout 0.5 or greater.

In the case of norelgestral, the stabilizing agent will generally bepresent in an amount ranging from about 0.5 to about 10 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 0.5 to about 8 wt. % on the same basis. Most preferably, it willbe present in an amount of about 0.5 to about 5 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to norelgestral isabout 0.5 or greater.

In the case of piroxicam, the stabilizing agent will generally bepresent in an amount ranging from about 0 to about 18 wt. % based uponthe weight of the adhesive material. Preferably, it will range fromabout 0 to about 13 wt. % on the same basis. Most preferably, it will bepresent in an amount of about 1 to about 12 wt. % on the same basis.Further, the weight ratio of the stabilizing agent to piroxicam is about0.5 or greater.

The adhesive layer may further comprise one or more pharmaceuticallyacceptable additives. Non-limiting examples of additives includecohesion-promoting additives, penetration enhancers, plasticizers,tackifiers, and similar additives. The substances suitable for thispurpose are known to those skilled in the art.

The amount of additives present in the adhesive layer range from about0.05% to about 40% by weight of the adhesive material, preferablyranging from about 1% to about 20%, and more preferably ranging fromabout 3% to about 20% by weight of the adhesive material. In embodimentscontaining more than one adhesive layer (i.e., having a first adhesivelayer and at least a second adhesive layer), the amounts and/or types ofadditives may be the same or different for each adhesive layer.

Non-limiting examples of cohesion promoting agents include colloidalsilicone dioxide, zinc oxide, polyvinylpyrrolidine, acrylate copolymers,crosspovidone, ethyl cellulose, acrylic copolymers, bentonites, clays,and mixtures thereof. In preferred embodiments, the cohesive promotingagent is colloidal silicon dioxide.

The amount of cohesion promoting agent present in the adhesive layerranges from about 0% to about 15% by weight of the adhesive material,preferably ranging from about 3% to about 10% by weight of the adhesivematerial, most preferably ranging from about 5% to about 8% by weight ofthe adhesive material. In embodiments containing more than one adhesivelayer, the amounts and/or types of cohesive promoting agent may be thesame or different for each adhesive layer.

Non-limiting examples of penetration enhancers include methyl laurate,ethyl oleate, glycerol mono oleate, oleic acid, oleyl alcohol, isopropylpalmitate, isopropyl myristate, octyldodecanol, ω-pendadecalactone,cyclopendadecanone, propylene glycol monolaurate, eucalyptol, Ceraphyl31, 1-dodecanol, transcutol P, triacetin, propylene glycol, dipropyleneglycol, butylene glycol, ethanol, octanol, limonene, sorbitanmonooleate, n-alkylphenol ether ethoxylates, n-alkyl ether ethoxylates,and mixtures thereof.

The amount of penetration enhancers present in the adhesive layer rangesfrom about 0% to about 40% by weight of the adhesive material,preferably ranging from about 0% to about 30% by weight of the adhesivematerial, most preferably ranging from about 0% to about 20% by weightof the adhesive material. In embodiments containing more than oneadhesive layer, the amounts and/or types of penetration enhancers may bethe same or different for each adhesive layer.

Non-limiting examples of plasticizers include mineral oil, siliconefluid, and mixtures thereof.

The amount of plasticizers present in the adhesive layer ranges fromabout 0% to about 40% by weight of the adhesive material, preferablyranging from about 0% to about 30% by weight of the adhesive material,most preferably ranging from about 0% to about 20% by weight of theadhesive material. In embodiments containing more than one adhesivelayer, the amounts and/or types of plasticizer may be the same ordifferent for each adhesive layer.

Non-limiting examples of tackifiers include silicone fluid, mineral oil,polybutenes, and mixtures thereof.

The amount of tackifier present in the adhesive layer ranges from about0% to about 40% by weight of the adhesive material, preferably rangingfrom about 0% to about 30% by weight of the adhesive material, mostpreferably ranging from about 0% to about 10% by weight of the adhesivematerial. In embodiments containing more than one adhesive layer, theamounts and/or types of tackifier may be the same or different for eachadhesive layer.

The inner-most layer of these solid dispersion transdermal deliverydevices is the protective release liner, 13, 24, or 35. This layer issituated adjacent to the side of the adhesive layer, away from thebacking layer. Prior to application and use of the solid dispersiontransdermal delivery device, the protective release liner is peeled awayfrom the adhesive layer/skin contact layer, 12, 23, or 34 and discarded.It provides a barrier to drug migration prior to the application of thedevice and is easily removable from the adhesive layer. The compositionof the protective release liner is not critical. Any well-known releaseliner layer which possesses these qualities can be used in the presentinvention. Typically, the release liner comprises a base film coatedwith silicone or fluoropolymer which is thermally cured or cured withultraviolet light in the presence of a photoinitiator/catalyst.

In a three-layer solid transdermal delivery device as depicted in FIG.1, only one adhesive layer, a drug reservoir adhesive layer 12, ispresent and located between a backing layer 11 and a protective releaseliner 13. In such embodiments, it is the drug reservoir adhesive layer12 which contacts and adheres to the skin subsequent to the removal ofthe release liner 13 and application of the device.

In a four-layer solid transdermal delivery device as depicted in FIG. 2,both a drug reservoir adhesive layer 22 and a skin contact adhesivelayer 23 are present and adjacent to each other. The drug reservoiradhesive layer 22 is located between the backing layer 21 and the skincontact adhesive layer 23, while the skin contact adhesive layer 23 islocated between the drug reservoir adhesive layer 22 and the protectiverelease liner 24. In such embodiments, the skin contact adhesive layer23 contacts and adheres to the skin subsequent to the removal of therelease liner 24 and application of the device.

In a five-layer solid transdermal delivery device as depicted in FIG. 3,both a drug reservoir adhesive layer 32 and a skin contact adhesivelayer 34 are present, but separated by a membrane layer 33. The drugreservoir adhesive layer is located between the backing layer 31 and themembrane layer 33, while the skin contact adhesive layer is locatedbetween the membrane layer 33 and the release liner 35. In suchembodiments, the skin contact adhesive layer 34 contacts and adheres tothe skin subsequent to the removal of the release liner 35 andapplication of the device.

As in a five-layer solid transdermal delivery device, embodimentscontaining two adhesive layers may further comprise a membrane, wovenmesh or non woven 33. The membrane 33 is located between the drugreservoir adhesive layer 32 and the skin contact adhesive layer 34. Themembrane layer may serve a variety of purposes, such as controllingdiffusion and providing controlled release of the active pharmaceuticalingredient(s). The membrane layer is selected such that it is ratecontrolling, i.e., the presence of the membrane layer in the device maychange the skin penetration profile of the device compared to a likedevice not having the membrane. The membrane, woven mesh or non wovenmay also serve as an anchorage layer between the two adhesive layers toreduce adhesive transfer.

Suitable membranes include continuous film membranes and microporousmembranes and may be of woven or non-woven material. The membrane ispreferably made of a flexible, polymeric material used conventionally bythose skilled in the art. Polymer films which may be used for making themembrane layer include, without limitation, those comprising low densitypolyethylene, high density polyethylene, ethyl vinyl acetate copolymers,polypropylene and other suitable polymers. In one embodiment, themembrane layer is a microporous film membrane prepared fromethylene:vinyl acetate copolymers containing from about 0.5 to about 28wt. % vinyl acetate. Suitable woven meshes include Saatifil® PES such asPES105/52 available from Saatitech, Inc. A suitable non woven isSontara® from DuPont Nonwovens Sontara Technologies.

In a preferred embodiment, the membrane layer is a microporouspolypropylene membrane, such as Celgard® 2400 (available from Celgard,Inc., Solupor; Cotran 9702, Cotran 9705, Cotran 9706, Cotran 9707,Cotran 9712Cotran 9715, Cotran 9716, Cotran 9728 (available from 3M™),and Solupor®10P05A (available from DSM SoluTech). The membrane thicknesscan generally range from about 10 μm to about 100 μm, preferably thethickness can range from about 15 μm to about 50 μm.

The present invention also relates to methods of manufacturing the solidtransdermal delivery devices described herein.

One embodiment is directed to a method of making a three-layeredtransdermal device 10 comprising a backing layer 11, an adhesive layer12 comprising a therapeutic agent in amorphous form and a stabilizingagent with a hydrogen bond-forming functional group capable of hydrogenbonding with the therapeutic agent, and a protective release liner 13.First, a drug reservoir adhesive layer is prepared by completelydissolving both the therapeutic agent and the polymeric stabilizer in asolvent to form a uniform solution and mixing the solution with anadhesive or adhesive solution to form a new solution or suspension andthen coating a release liner with the solution or suspension. Thesolution or suspension may also contain optional ingredients such as apenetration enhancer. The coated release liner is then dried to form adry adhesive. The dry adhesive is then laminated to a backing film toform the three-layered film. Individual devices (or patches) containingthe three layers are die-cut from the laminate. Traditional methodsknown in the art can be used to die-cut the layers from the laminate.Another embodiment is directed to a method of manufacturing atransdermal drug delivery device comprising a) mixing a first uniformsolution comprising a first therapeutic agent in amorphous form and afirst combination polymeric stabilizing and dispersing agent comprisinga hydrogen bond-forming functional group with (ii) a first adhesive oradhesive solution to form a second solution or suspension, (b) coating arelease liner with the second solution or suspension to form a firstcoated release liner, and (c) drying the first coated release liner.

In another embodiment is a method of making a four-layered transdermaldevice 20 comprising a drug reservoir layer 22, and a skin contact layer23, each comprising a therapeutic agent in amorphous form and astabilizing agent with a hydrogen bond-forming functional group capableof hydrogen bonding with the therapeutic agent, a backing layer 21, anda protective release liner 24. First, a drug reservoir adhesive layer ona release liner is prepared. A drug reservoir adhesive layer is preparedby completely dissolving both the therapeutic agent and the polymericstabilizer in a solvent to form a uniform solution and mixing thesolution with an adhesive or adhesive solution to form a new solution orsuspension and then coating a release liner with the solution orsuspension. The solution or suspension may also contain optionalingredients such as a penetration enhancer. The coated release liner isthen dried to form a dry adhesive. The dry adhesive is then laminated toa backing film to form the three-layered film.

Second, a skin contact adhesive layer on a release liner is prepared. Askin contact adhesive layer is prepared by completely dissolving boththe therapeutic agent and the polymeric stabilizer in a solvent to forma uniform solution and mixing the solution with an adhesive or adhesivesolution to form a new solution or suspension and then coating a releaseliner with the solution or suspension. The solution or suspension mayalso contain optional ingredients such as a penetration enhancer. Thecoated release liner is then dried to form a dry adhesive.

Finally, to form the four-layer laminate, the available sides of theskin contact adhesive layer and drug reservoir layer are laminatedtogether. Individual devices (or patches) containing the four layers aredie-cut from the laminate. Traditional methods known in the art can beused to die-cut the layers from the laminate.

Another embodiment comprises a method of manufacturing a transdermaldrug delivery device comprising: (a) mixing (i) a first uniform solutioncomprising a first therapeutic agent in amorphous form and a firstcombination polymeric stabilizing and dispersing agent comprising ahydrogen bond-forming functional group with (ii) a first adhesive oradhesive solution to form a second solution or suspension, (b) coating arelease liner with the second solution or suspension to form a firstcoated release liner, and (c) drying the first coated release liner.

In another embodiment is a method of making a five-layered transdermaldevice 30 comprising a drug reservoir layer 32, and a skin contact layer34, each comprising a therapeutic agent in amorphous form and astabilizing agent with a hydrogen bond-forming functional group capableof hydrogen bonding with the therapeutic agent, a membrane 33 sandwichedbetween the drug reservoir layer 32 and skin contact layer 34, a backinglayer 31, and a protective release liner 35. First, a drug reservoiradhesive layer on a release liner is prepared. A drug reservoir adhesivelayer is prepared by completely dissolving both the therapeutic agentand the polymeric stabilizer in a solvent to form a uniform solution andmixing the solution with an adhesive or adhesive solution to form a newsolution or suspension and then coating a release liner with thesolution or suspension. The solution or suspension may also contain askin penetration enhancer. The coated release liner is then dried toform a dry adhesive. The dry adhesive is then laminated to a backingfilm to form the three-layered film. The release liner is then peeledoff leaving a drug reservoir adhesive layer on a backing film.

In another embodiment is a method of manufacturing a transdermal drugdelivery device comprises: (a) mixing (i) a first uniform solutioncomprising a first therapeutic agent in amorphous form and a firstcombination polymeric stabilizing and dispersing agent comprising ahydrogen bond-forming functional group with (ii) a first adhesive oradhesive solution to form a second solution or suspension, (b) coating arelease liner with the second solution or suspension to form a firstcoated release liner, and (c) drying the first coated release liner.This method further comprises: (a′) mixing (i) a second uniform solutioncomprising a second therapeutic agent in amorphous form, which may bethe same as or different from the first therapeutic agent, and a secondcombination polymeric stabilizing and dispersing agent, which may be thesame as or different from the first combination stabilizing anddispersing agent, comprising a hydrogen bond-forming functional groupwith (ii) a second adhesive or adhesive solution, which may be the sameas or different from the first adhesive or adhesive solution, to form athird solution or suspension, (b′) coating a second release liner, whichmay be the same as or different from the first release liner, with thethird solution or suspension, (c′) drying the coated second releaseliner, (d) laminating the first dried coated release liner onto one sideof a membrane, woven mesh, or non-woven mesh, and (e) laminating thesecond dried coated release liner onto the second side of the membrane,woven mesh, or non-woven mesh.

The skin contact adhesive layer and drug reservoir layer can besimultaneously laminated to the membrane, woven mesh, or non woven. Forthis simultaneous lamination, the skin contact adhesive layer is firstprepared by completely dissolving both the therapeutic agent and thepolymeric stabilizer in a solvent to form a uniform solution. Thissolution is mixed with an adhesive or adhesive solution to form a newsolution or suspension. The solution or suspension may also containoptional components such as a penetration enhancer. The solution orsuspension is then coated onto the release liner. The coated releaseliner is then dried to form a dry adhesive. A membrane, woven mesh, ornon woven is then laminated to the available side of the skin contactadhesive layer and at the same time, the drug reservoir adhesive layeris laminated to the other side of the membrane, woven mesh, or non wovento form a five layer laminate. Individual devices (or patches)containing five layers are die-cut from the laminate.

For non-simultaneous lamination, a laminate having a membrane, a skincontact adhesive layer, and a release liner is prepared. The skincontact adhesive layer is prepared by completely dissolving both thetherapeutic agent and the polymeric stabilizer in a solvent to form auniform solution. This solution is mixed with an adhesive or adhesivesolution to form a new solution or suspension. The solution orsuspension may also contain optional components such as a penetrationenhancer. The solution or suspension is then coated onto the releaseliner. The coated release liner is then dried to form a dry adhesive. Amembrane is then laminated to the available side of the skin contactadhesive layer. Finally, to form the five-layer laminate, the availableside of the membrane from the skin contact adhesive laminate islaminated to the available side of the drug reservoir adhesive layer.Individual devices (or patches) containing five layers are die-cut fromthe laminate. Traditional methods known in the art can be used todie-cut the layers from the laminate.

In carrying out the procedures of the present invention, it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented. Forexample, it is often possible to substitute one buffer system or culturemedium for another and still achieve similar, if not identical, results.Those of skill in the art will have sufficient knowledge of such systemsand methodologies so as to be able, without undue experimentation, tomake such substitutions as will optimally serve their purposes in usingthe methods and procedures disclosed herein.

The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

The entire disclosures of all applications, patents and publications,cited above and below, are hereby incorporated by reference in theirentirety.

The following examples further illustrate the invention and its uniquecharacteristics. These examples are not intended to limit the inventionin any manner.

EXAMPLES

Examples 1 to 9: Solid dispersion of scopolamine transdermal systemcontaining a stable amorphous form of scopolamine and a polymericdispersant and stabilizer capable of forming hydrogen bond withscopolamine.

Example 1: To a glass jar Plastone 29/32 (12 g) and ethanol (7.56 g)were added. The admixture was mixed with a spatula, heated and sonicatedin a water bath at 45° C. until a viscous solution was formed. To thesolution was added scopolamine base (4.00 g). The admixture was mixedwith a spatula, heated, sonicated and swirled until a clear viscoussolution was formed. After the solution was cooled for a while, DowCorning silicone adhesive 7-4302 (40.82 g, 60% solid) and ethyl acetate(8.34 g) were added. The material was quickly mixed at high shear toprovide a cream-like uniform suspension. After air bubbles were removedby rolling overnight, the suspension was coated to a release liner,dried at room temperature for 5 minutes, in an oven set at 40° C. for 5minutes and in an oven set at 85° C. for 5 minutes to form a thin layerof adhesive on release liner. A backing film Mediflex® 1502 waslaminated to the adhesive side. Individual patches were die-cut andpouched. The resulting adhesive layer between the backing and releaseliner was opaque, free of scopolamine crystals as observed bymicroscopic analysis. DSC analysis of die-cut patches indicated thescopolamine was in amorphous form dispersed within the Plastone (PVP)matrix which was dispersed within the silicone adhesive matrix. Thedispersed amorphous scopolamine in the patch had a glass transitiontemperature (Tg) of 29° C. The glass transition temperature ofundispersed amorphous scopolamine is about 10° C. The higher glasstransition temperature of the dispersed amorphous scopolamine is theresult of the intermolecular interactions between the dispersant PVP andscopolamine molecules including hydrogen bonding. X-ray diffractionindicated scopolamine was in amorphous form in the patch. The in vitroflux study indicated 211 μg/cm² was delivered within 72 hours. The fluxof this solid transdermal system containing stable amorphous form ofscopolamine is much higher than the flux of a crystalline scopolamineformulation (88 μg/cm²).

Individual pouched patches were stored at 40° C. and room temperature.After 8 months at 40° C. or 19 months at room temperature, no crystalswere observed by microscopic and DSC and X-ray powder diffractionanalyses, indicating scopolamine remained in amorphous form in thepatch.

TABLE 1 Solid dispersion scopolamine transdermal system summaryCompletely present in dispersed In vitro Completely amorphous form inaged sample PVP/ flux at Presence present as 8 19 6 6 Ex. scop 72 hr.,of Amorphous month month month month No. Composition ratio μg/cm²crystals form, time 0 at 40° C. at RT at 40° C. at RT 1 10% scop, 3 to 1211 No Yes Yes Yes Yes Yes 30% PVP, 60% silicone adhesive 2 10% scop, 2to 1 463 No Yes Yes Yes Yes Yes 20% PVP, 70% silicone adhesive 3  5%scop, 2 to 1 295 No Yes Yes Yes 10% PVP, 80% silicone adhesive,  5%silicone fluid 4  4% scop, 2 to 1 249 No Yes Yes Yes  8% PVP, 88%silicone adhesive 5  4% scop, 2 to 1 213 No Yes Yes Yes  8% PVP, 83%silicone adhesive,  5% silicone fluid 6  6% scop, 2 to 1 271 No Yes YesYes 12% PVP, 82% silicone adhesive 7  6% scop, 2 to 1 251 No Yes Yes Yes12% PVP, 77% silicone adhesive,  5% silicone fluid 8  5% scop, 2 to 1307 No Yes Yes Yes 10% PVP, 85% silicone adhesive 9  6% scop, 2 to 1 627No Yes Yes Yes 12% PVP, 79% silicone adhesive,  3% silicone fluid

The data in Table 1 indicates a weight ratio of PVP to scopolamine of 2to 1 is sufficient to stabilize the dispersed scopolamine amorphous formfor a long period of time.

Example 10 to 15: Solid dispersion of natrexone transdermal systemcontaining a stable amorphous form of naltrexone and a polymericdispersant and stabilizer capable of forming hydrogen bond withnaltrexone. The data in Table 2 indicates that naltrexone whoseamorphous form has a higher glass transition temperature (79.5° C.) thanthe glass transition temperature of amorphous scopolamine requires lessPVP to disperse and stabilize it. The solid dispersion transdermalsystems have higher flux than the crystalline suspension transdermalsystem example 15.

TABLE 2 Solid dispersion naltrexone transdermal system summaryCompletely present in In vitro Completely dispersed PVP/ flux atPresence present as Amorphous form Ex. scop 168 hr., of Amorphous inaged sample- No. Composition ratio μg/cm² crystals form time 0? 1 month10 15% NTX, 20% PVP, 1.3 to 1    488 No Yes Yes 65% silicone 7-4302 1110% NTX, 10% PVP, 1 to 1  279 No Yes Yes 80% silicone 7-4301 12 10% NTX,10% PVP, 1 to 1 1185 No Yes Yes 45% silicone 7-4302, 35% dodecanol 1315% NTX, 15% PVP, 1 to 1 1297 No Yes Yes 35% silicone 7-4302, 35%dodecanol 14 20% NTX, 20% PVP, 1 to 1  669 No Yes Yes 35% acrylic87-2979, 25% dodecanol 15 15% NTX, 0 to 1  106 Yes No No 85% acrylic87-2979

The data in Table 2 indicates a weight ratio of PVP to naltrexone of 1to 1 is sufficient to stabilize the dispersed naltrexone amorphous formfor a long period of time.

1. A transdermal drug delivery device comprising: (a) a backing film;(b) a first adhesive layer comprising a solid dispersion, saiddispersion comprising: an first adhesive, a first therapeutic agent inamorphous form, and a first combination polymeric stabilizing anddispersing agent comprising a hydrogen bond-forming functional group;and (c) a protective release liner.
 2. The drug delivery device of claim1, having a weight ratio of said polymeric stabilizing/dispersing agentto said therapeutic agent in amorphous form of at least 0.5.
 3. The drugdelivery device of claim 1, wherein at least 95% of said therapeuticagent is in amorphous form after storage at room temperature for atleast six months.
 4. The drug delivery device of claim 3, wherein atleast 99% of said therapeutic agent is in amorphous form after storageat room temperature for at least six months.
 5. The drug delivery deviceof claim 4, wherein at least 99% of said therapeutic agent is inamorphous form after storage at room temperature for at least 18 months.6. The drug delivery device of claim 1, wherein said therapeutic agenthas a skin absorption rate which is increased by at least 50% comparedto the skin absorption rate of said therapeutic agent in an identicaltransdermal drug delivery without said polymeric stabilizing/dispersingagent.
 7. The drug delivery device of claim 1, wherein said therapeuticagent is selected from the group consisting of (i) scopolamine,oxybutynin, naltrexone, testosterone, estradiol, rotigotine, fentanyl,ethinyl estradiol, or norelgestral, (ii) any pharmaceutically acceptablesalts of any of (i), or any combination of any of (i), (ii), or (i) and(ii).
 8. The transdermal drug delivery device of claim 1, furthercomprising (d) a second adhesive layer between said first adhesive layerand said protective release liner, said second adhesive layercomprising: a second adhesive which may be the same as or different fromsaid first adhesive, a second therapeutic agent in amorphous form whichmay be the same as or different from said first therapeutic agent, and asecond combination polymeric stabilizing and dispersing agent which maybe the same as or different from said first combination polymericstabilizing and dispersing agent, said agent comprising a hydrogenbond-forming functional group.
 9. The drug delivery device of claim 8,further comprising: (e) a membrane between said first and secondadhesive layers.
 10. The drug delivery device of claim 1, wherein saidfirst adhesive layer further comprises a member selected from the groupconsisting of a skin penetration enhancer, a tackifier, a cohesivepromoter, and any combination of any of the foregoing.
 11. The drugdelivery device of claim 8, wherein said first, second, or first andsecond adhesive layers independently further comprise a member selectedfrom the group consisting of a skin penetration enhancer, a tackifier, acohesive promoter, and any combination of any of the foregoing.
 12. Thedrug delivery device of claim 1, wherein said therapeutic agent inamorphous form contains at least one hydrogen bond-forming group. 13.The drug delivery device of claim 12, wherein there is one or morehydrogen bonds between said therapeutic agent in amorphous form and saidpolymeric stabilizing/dispersing agent and wherein said drug deliverydevice has greater dispersion capability compared to an identicaltransdermal drug delivery device without said polymericstabilizing/dispersing agent.
 14. The drug delivery device of claim 1,having a weight ratio of polymeric stabilizing/dispersing agent totherapeutic agent in amorphous form of 0.5 or greater.
 15. The drugdelivery device of claim 1, having a weight ratio of said polymericstabilizing agent to said therapeutic agent in amorphous form of 2 orgreater, and wherein said therapeutic agent in amorphous form has aglass transition temperature of less than 50° C.
 16. The drug deliverydevice of claim 15, having a weight ratio of polymeric stabilizing agentto therapeutic agent in amorphous form between 2 and 10, and whereinsaid therapeutic agent in amorphous form has a glass transitiontemperature of less than 40° C.
 17. The drug delivery device of claim 1,having a weight ratio of said polymeric stabilizing agent to saidtherapeutic agent in amorphous form of 0.5 or greater, and wherein saidtherapeutic agent in amorphous form has a glass transition temperatureof at least 60° C.
 18. The drug delivery device of claim 17, having aweight ratio of said polymeric stabilizing agent to said therapeuticagent in amorphous form between 0.5 and 10, and wherein said therapeuticagent in amorphous form has a glass transition temperature of at least70° C.
 19. The drug delivery device of claim 18, having a weight ratioof said polymeric stabilizing agent to said therapeutic agent inamorphous form between 0.5 and
 2. 20. The drug delivery device of claim1, wherein said a therapeutic agent in amorphous form contains less than1.0% crystallinity.
 21. The drug delivery device of claim 1, whereinsaid adhesive layer comprises from about 0.05 to about 40 weight % ofsaid therapeutic agent.
 22. The drug delivery device of claim 1, whereinsaid adhesive layer comprises from about 1 to about 20 weight % of saidtherapeutic agent in amorphous form.
 23. The drug delivery device ofclaim 1, wherein said adhesive is selected from the group consisting ofa polysiloxane, polyisobutylene, an acrylic adhesive, or any combinationof any of the foregoing.
 24. A method of manufacturing a transdermaldrug delivery device, said method comprising: (a) mixing (i) a firstuniform solution comprising a first therapeutic agent in amorphous formand a first combination polymeric stabilizing and dispersing agentcomprising a hydrogen bond-forming functional group with (ii) a firstadhesive or adhesive solution to form a second solution or suspension,(b) coating a release liner with said second solution or suspension toform a first coated release liner, and (c) drying said first coatedrelease liner.
 25. The method of claim 24, further comprising the stepof: (d) laminating the dry coated release liner onto a backing film. 26.The method of claim 24, further comprising the step of: (e) die-cuttingone or more unit dosage forms from the laminate.
 27. The method of claim24, wherein one or more of said uniform solution, adhesive, adhesivesolution, second solution or suspension independently further comprisesa member selected from the group consisting of a skin penetrationenhancer, a tackifier, a cohesive promoter, or a combination of any ofthe foregoing.
 28. The method of claim 24, further comprising (a′)mixing (i) a second uniform solution comprising a second therapeuticagent in amorphous form, which may be the same as or different from saidfirst therapeutic agent, and a second combination polymeric stabilizingand dispersing agent, which may be the same as or different from saidfirst combination stabilizing and dispersing agent comprising a hydrogenbond-forming functional group with (ii) a second adhesive or adhesivesolution, which may be the same as or different from said first adhesiveor adhesive solution, to form a third solution or suspension, (b′)coating a second release liner, which may be the same as or differentfrom said first release liner, with said third solution or suspension,(c′) drying the coated second release liner, (d) laminating the firstdried coated release liner onto a backing film, (e) removing said firstrelease liner from said first coated release liner to form a first driedcoating layer, and (f) laminating the second dried coated release linerto said first dried coating layer.
 29. The method of claim 28, whereinone or more of said first uniform solution, first adhesive or adhesivesolution, second solution or suspension, second uniform solution, secondadhesive or adhesive solution, or third solution or suspensionindependently further comprises a member selected from the groupconsisting of a skin penetration enhancer, a tackifier, a cohesivepromoter, and any combination of any of the foregoing.
 30. The method ofclaim 24, further comprising: (a′) mixing (i) a second uniform solutioncomprising a second therapeutic agent in amorphous form, which may bethe same as or different from said first therapeutic agent, and a secondcombination polymeric stabilizing and dispersing agent, which may be thesame as or different from said first combination stabilizing anddispersing agent, comprising a hydrogen bond-forming functional groupwith (ii) a second adhesive or adhesive solution, which may be the sameas or different from said first adhesive or adhesive solution, to form athird solution or suspension, (b′) coating a second release liner, whichmay be the same as or different from said first release liner, with saidthird solution or suspension, (c′) drying the coated second releaseliner, (d) laminating the first dried coated release liner onto one sideof a membrane, woven mesh, or non-woven mesh, and (e) laminating thesecond dried coated release liner onto the second side of said membrane,woven mesh, or non-woven mesh.
 31. The method of claim 30, wherein steps(d) and (e) occur simultaneously.
 32. The method of claim 30, whereinstep (d) occurs before step (e).
 33. The method of claim 30, wherein oneor more of said first uniform solution, first adhesive or adhesivesolution, second solution or suspension, second uniform solution, secondadhesive or adhesive solution, or third solution or suspensionindependently further comprises a member selected from the groupconsisting of a skin penetration enhancer, a tackifier, a cohesivepromoter, and any combination of any of the foregoing.